Stroke is the major cause of an adult disability epidemic in the US, with a major contribution from post-stroke cognitive impairment and dementia (PSCID), the rates of which are disproportionally high among the health disparity populations. Despite the PSCID?s overwhelming impact on public health, a knowledge gap exists with regard to the complex interaction between the acute stroke event and highly prevalent pre-existing brain pathology related to cerebrovascular (VCID) and Alzheimer?s disease, or related dementia (AD/ADRD). Understanding the factors that modulate PSCID risk in relation to index stroke event is critically important for developing personalized prognostication of PSCID, targeted interventions to prevent PSCID, and informing future clinical trial design. In response to this critical challenge, we propose Determinants of Incident Stroke Cognitive Outcomes and Vascular Effects on RecoverY (DISCOVERY), a collaborative network of clinical sites with access to acute stroke populations and the expertise and capacity for systematic assessment of PSCID led by a team of recognized experts in VCID, AD, acute stroke, health disparities, and multi-center research. The overarching goal of this proposal is to determine which specific subsets of stroke events cause (or do not cause) PSCID and which additional demographic (sex, race, ethnicity), clinical factors and comorbidities that synergize with acute stroke to result in or prevent PSCID. The overall scientific objective of this study is to elucidate mechanisms of brain resilience/susceptibility to PSCID in diverse US populations based on complex interplay between life-course exposure to multiple vascular risk factors, pre-existing burden of microvascular and neurodegenerative pathology, the effect of strategic acute stroke lesions, and the mediating effect of genomic/epigenomic variation. We will achieve this goal by implementing the DISCOVERY Network of 30 clinical sites, which under the leadership of the Administrative Core and guided by the research strategy delineated by the Recruitment and Retention, Statistics, and Repository Cores, will conduct a prospective, multi- center, observational, nested-cohort study of 8,000 nondemented ischemic and hemorrhagic incident stroke patients within 72 hours of symptom onset, who will be followed for a minimum of 2 years, with serial cognitive evaluations and assessments of functional outcome, with subsets undergoing research MRI and PET and comprehensive genetic/genomic and fluid biomarker testing. In a series of systematic, hypothesis driven experiments we will: 1) identify the independent and combined effect of the acute stroke lesion, pre-existing burden of disease, and baseline markers of brain resilience on PSCID; 2) examine the role of acute stroke as a critical factor in accelerating AD/ADRD and VCID pathology leading to PSCID; and 3) develop two distinct generalizable personalized-medicine models for individual patient outcome prediction and patient selection for clinical trials. DISCOVERY will become a landmark study to unravel the mechanisms of post-stroke cognitive disability, early stroke recovery, and potential targets for personalized prevention, intervention, and rehabilitation.